Arab Journal of Urology (2013) 11, 2732

Arab Journal of Urology

(Ofcial Journal of the Arab Association of Urology)
www.sciencedirect.com

PEDIATRIC UROLOGY
REVIEW

Disorders of sexual dierentiation: II. Diagnosis

and treatment
Mohamed El-Sherbiny *

McGill University, Montreal Childrens Hospital, Quebec, Canada

Received 11 September 2012, Received in revised form 3 November 2012, Accepted 8 November 2012
Available online 10 January 2013

KEYWORDS Abstract Objectives: To provide a review and summary of recent advances in the
Diagnosis; diagnosis and management of disorder(s) of sexual differentiation (DSD), an area
Management; that has developed over recent years with implications for the management of chil-
Ambiguous genitalia; dren with DSD; and to assess the renements in the surgical techniques used for gen-
Intersex; ital reconstruction.
Genitogram; Methods: Recent publications (in the previous 10 years) were identied using
Endocrine assessment; PubMed, as were relevant previous studies, using following keywords; diagnosis
Gender assignment; and management, ambiguous genitalia, intersex, disorders of sexual differentia-
Genitoplasty; tion, genitogram, endocrine assessment, gender assignment, genitoplasty, and
Urogenital sinus urogenital sinus. The ndings were reviewed.
Results: Arbitrary criteria have been developed to select patients likely to have
ABBREVIATIONS DSD. Unnecessary tests, especially those that require anaesthesia or are associated
with radiation exposure, should be limited to situations where a specic question
DSD, disorder(s) of needs to be answered. Laparoscopy is an important diagnostic tool in selected
sexual differentiation; patients. The routine use of multidisciplinary diagnostic and expert surgical teams
CAH, congenital adre- has become standard. Full disclosure of different therapeutic approaches and their
nal hyperplasia; MIS, timing is recommended.
Mullerian-inhibiting Conclusions: Diagnostic tests should be tailored according to the available
substance; PAIS, par- information. Parents and/or patients should be made aware of the paucity of
tial androgen insensi-
tivity; GD, gonadal
* Address: Paediatric Surgery (Urology), Montreal Childrens Hos-
pital, C527-2300 Rue Tupper, Montreal, Quebec, Canada H3H1P3.
Tel.: +1 514 4124366.
E-mail address: mohamed.el-sherbiny@muhc.mcgill.ca
Peer review under responsibility of Arab Association of Urology.

Production and hosting by Elsevier

2090-598X 2012 Arab Association of Urology. Production and hosting by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.aju.2012.11.008
28 El-Sherbiny

dysgenesis; CAIS,
complete androgen
insensitivity syndrome;
UGS, urogenital sinus;
TUM, total UGS mo-
bilisation; ASTRA,
anterior sagittal trans-
rectal approach
well-designed studies, as these conditions are rare. Unnecessary irreversible surgery
should be postponed until a multidisciplinary experienced team, with the parents
and or patients approval, can make a well-judged decision.
2012 Arab Association of Urology. Production and hosting by Elsevier B.V.
All rights reserved.

Diagnosis the PVE classication for genital ambiguity, where P

There are four general concepts and goals in the diagno-
sis of disorders of sexual differentiation (DSD): (1) The
urgent detection of underlying endocrinopathies; (2)
Gender assignment must be avoided before an expert
evaluation in newborns, which usually requires a few
weeks; (3) The evaluation and long-term management
must be undertaken at a centre with an experienced mul-
tidisciplinary team; and (4) Open communication with
patients and families is essential, participation in deci-
sion-making is to be encouraged, and ample time and
opportunity should be made for continued discussion.
Presentation and clinical evaluation
The presentation of DSD can be at birth or later in life
(Table 1); the clinical evaluation is shown in Table 2.
The stage of female virilisation can be assessed using
the Prader scale [1]. The Quigley scale is used for assess-
ing the development of external genitalia in 46,XY chil-
dren with DSD [2]. Recently, Rink et al. [3] developed
Table 1 The presentation of DSD.
Period Signs/symptoms
Neonatal
1. Overt genital ambiguity (e.g. cloacal exstrophy)
2. Apparent female genitalia:
Enlarged clitoris > 9 mm
Posterior labial fusion: Anogenital ratio, anus to
posterior fourchette/anus and the base of the
clitoris is > 0.5
Inguinal/labial mass
3. Apparent male genitalia:
Bilateral impalpable testes
Mild hypospadias with undescended testes
(palpable or not)
Perineal hypospadias with bid scrotum
Micropenis < 1.9 cm
4. A family history of DSD (CAIS)
5. Genital and karyotype discordance
Older individuals
1. Unrecognised genital ambiguity
2. Inguinal hernia in a female
3. Delayed/incomplete puberty
Virilisation in a female
Primary amenorrhoea
Male breast development
Gross haematuria in a male
represents stretched phallic length and width, V is the
distance from the bladder neck to the vagina and the dis-
tance from the vagina to the perineal meatus, and E is
the Prader number. This classication system was found
to aid in the surgical planning and the analysis of surgi-
cal outcomes.
Laboratory evaluation
First-line testing in newborns includes karyotyping with
X- and Y-specic probe detection (even when a prenatal
karyotype is available). The results of karyotyping can
take 23 days. Fluorescence in situ hybridisation can
be used to identify X and Y chromosomes within a
few hours. The laboratory evaluation should also
include an assay for serum electrolytes, to exclude a
salt-wasting form of congenital adrenal hyperplasia
(CAH), a measurement of 17-hydroxyprogesterone
(usually after 48 h to avoid interference with maternal
progesterone), testosterone, gonadotrophins, and
Mullerian-inhibiting substance (MIS). Urine analysis is
also required to exclude proteinuria associated with
Denys Drash syndrome.
Radiology
The radiological assessment can include ultrasonogra-
phy, MRI or CT, and a retrograde genitogram (Fig. 1)
to assess the Mullerian structures and the kidneys. In
a recent study the role of the genitogram during the pre-
operative evaluation in females with CAH has been
evaluated. Genitography did not reveal the urogenital
sinus (UGS) anatomy completely in 25% of the patients
[4]. However, a well-conducted genitogram shows
important anatomical details that can be used in opera-
tive planning and eliminates the need for an endoscopic
examination in a separate session.
Because of radiation exposure and the need for seda-
tion the use of CT and MRI should be reserved for pa-
tients with suspect or inconclusive ndings on
ultrasonography.
Endoscopy, laparoscopy and gonadal biopsy
Preoperative endoscopy and laparoscopy (See Video 1)
can provide useful anatomical details that can help in
Disorders of sexual differentiation: II. Diagnosisand treatment 29

Table 2 Clinical evaluations of DSD.

Evaluation Finding
History
1. The maternal history of androgen exposure
2. A family history of neonatal death might indicate CAH
3. History of consanguinity, autosomal recessive disorder
4. Family history of females who are childless or have amenorrhoea (CAIS)
Physical examination
1. The gonads
a. If the gonads are palpable CAH can be excluded.
b. Ovotestes can be suspected by asymmetry of tissue texture of the poles of the gonad
c. Impalpable gonads raise the possibility of a virilised female with CAH
2. Rugated scrotum with increased pigmentation raises the possibility of CAH
3. Normal phallic length in a newborn, measured when stretched from the penopubic junction
to the tip of the glans, should be P 2.5 cm and the normal diameter P 0.9 cm
4. Normal clitoral width 26 mm; clitoral length > 9 mm is unusual
5 Anogenital ratio: if >0.5 indicates virilisation

the diagnosis and surgical planning [4]. The presence of
a cervix and a uterus exclude 46,XY DSD, except for
persistent Mullerian duct syndrome and dysgenetic go-
nads. Preoperative endoscopy is considered an integral
part of genitoplasty, as it facilitates the insertion of a
Fogarty balloon catheter. A biopsy as well as laparos-
copy is not required when the diagnosis is clearly estab-
lished biochemically or by gene studies, as the histology
can be condently predicted. It is only required when an
ovotestis or dysgenetic gonad is suspected, to determine
the denitive diagnosis [5].
Gender assignment
This should be based on the judgement of a multidisci-
plinary team including paediatric subspecialists in endo-
crinology, urology, psychology, genetics, neonatology,
social work, nursing, and medical ethics [6,7]. The
assignment depends on many factors, including the
genes involved. Despite the signicant progress made
over recent years in understanding the genetic basis of
human sexual development, a specic molecular diagno-
sis is identied in about 20% of cases of DSD. Most vir-
ilised 46,XX infants will have CAH. By contrast, only
half of 46,XY children with DSD will be given a deni-
tive diagnosis [8,9]. Nevertheless, the molecular diagno-
sis alone cannot dictate the gender assignment. There
are several other factors that cannot be ignored,
including genital appearance, prenatal androgen expo-
sure, surgical options, the need for lifelong hormone
therapy, fertility potential, family wishes, and social
circumstances.
Disorders that are preferably raised as males are:
(1) XY karyotype, relative virilisation, partial androgen
insensitivity (PAIS), 5a-reductase or 17b-hydroxysteroid
dehydrogenase deciency.
a. At puberty, two-thirds of those reared as females virilise
and live as males [10].
b. Fertility is possible in 5a-reductase deciency [10].
c. Dissatisfaction is reported by 25% of patients with PAIS
regardless of sex of rearing [11].
(2) Micropenis and 46,XY cloacal exstrophy [12].
(3) 46,XX CAH in older patients who have normal male
external genitalia but with a delayed diagnosis. By con-
trast, evidence supports the current recommendation to
raise markedly virilised 46,XX newborns with CAH as
female [13].
Disorders that are preferably raised as females are:
(1) 46,XY individuals with PAIS or genital gonadal dysgen-
esis (GD) with poorly virilised genitalia [11].
(2) 46,XX individuals with CAH with milder degrees of
virilisation [13].
(3) All patients with 46,XY CAIS with no ambiguous geni-
talia who were assigned as female in infancy. All such
patients later identify themselves as females [14].
Surgical management
Feminising genitoplasty: The genitalia are reconstructed
at 26 months old; reconstruction in early infancy is rel-
atively easier due to the advantageous effects of mater-
nal oestrogen on tissue. Moreover, the potential
complications related to the continuity between the uri-
nary tract and peritoneum via the Fallopian tubes are
circumvented. However, minor surgical revisions might
be needed at the time of puberty [15]. These rened sur-
gical procedures are mainly used for vaginal stenosis, as
vaginal dilatation is not advisable before puberty. The
efcacy of early (<12 months old) vs. late surgery (in
adolescence and adulthood) has not been evaluated in
controlled clinical trials. Preoperative preparation
should include antibiotics and a steroid-stress dose
[16]. A rectal enema can be also used. Reconstruction in-
cludes three components, i.e. clitoroplasty, labioplasty
and vaginoplasty. Postnatal steroid therapy seems to
be associated with an improvement in the external
appearance of genitalia in patients with less severe
30 El-Sherbiny

clitoromegaly [17]. Thus clitoroplasty may only be used

in severe cases (Prader IIIV) and be done at the same
time as the common UGS repair. Clitoroplasty should
respect the innervation and vascularity, to preserve not
only the appearance but also the function (Fig. 2).
The technique of vaginoplasty depends on the loca-
tion of the conuence in relation to the bladder neck,
which is a more critical factor than the length of the
common channel [18]. The cutback vaginoplasty is
appropriate only for simple cases. The perineal omega-
shaped skin-ap vaginoplasty is applicable to a low con-
uence and as an adjunct to other forms of vaginoplasty
[19]. Total UGS mobilisation (TUM) (Fig. 3) is particu-
larly useful in those with a low and intermediate conu-
ence [16,18]. Figure 2 Clitoroplasty: Note the preservation of the dorsal
Partial UGS mobilisation with a limited anterior dis- neurovascular bundle and the sensitive mucosal collar around the
section to the inferior border of pubis has been reported glans of the clitoris.
to be equivalent to TUM, but with less risk of urinary
incontinence [20]. The pull-through vaginoplasty is
used for a very high conuence [16].
Recently, Pippi Salle et al. [21] reported the surgical
outcome of the anterior sagittal transrectal approach
(ASTRA) in the management of patients with a high

Figure 3 TUM: Note the conuence between the vagina and the
urethra, as indicated by the Fogarty catheter balloon, was brought
down to the level of the perineum.

UGS. ASTRA was found to be useful in providing opti-

Figure 1 A genitogram in a patient with Prader 4 CAH, showing
the anatomy of the UGS. Note that distance number 5 indicates
the length of the conuence of the urethra and the vagina to the
perineum, and distance number 4 is the urethral length.
mal exposure, facilitating vaginal dissection and separa-
tion from the urethra, and allowing reconstruction of
the bladder neck musculature, with minimal morbidity.
Complete vaginal replacement can be achieved by sev-
eral techniques, including replacement by intestine [22],
skin, or more recently, oral mucosa free grafts [23].
Disorders of sexual differentiation: II. Diagnosisand treatment
Complete vaginal replacement is usually required in
patients with vaginal agenesis. With the current use of
vaginal dilators, few women with CAIS need surgery
to lengthen the vagina [24]. If vaginoplasty is the only
indicated operation, delaying it until puberty can mini-
mise the complications [22].
Despite the great advances in medical and surgical
care for this rare disease, women with CAH still have
major sexual and reproductive functional decits [25].
Gastaud et al. [25] evaluated the long-term outcome
of 35 women with CAH (Prader stages IV) who
had been treated from birth to adolescence in the
same clinics. None of the women (when aged 18
43 years) expressed doubts about their gender assign-
ment. However, homosexual inclinations were noted
in 20% and more than a third of the patients had
never had heterosexual intercourse with vaginal
penetration. Moreover, most (81%) of those who
had vaginal penetration experienced pain. Only 17%
(six of 35) had children.
Masculinising genital surgery is surgically more chal-
lenging than feminising genitoplasty [11]. Different
innovative surgical approaches have been described for
repairing severe hypospadias with chordee correction.
Preoperative testosterone can be given to facilitate sur-
gery. In some cases an adult-sized testicular implant
can be inserted after sufcient pubertal scrotal develop-
ment [26]. The prophylactic removal of asymptomatic
discordant structures, such as a utriculus or Mullerian
remnants, is indicated only if they become symptomatic.
The surgical outcome in under-masculinised males is
variable and depends on the severity of the hypospadias
and the adequacy of phallic size.
Summary
Great advances have been made over recent years in the
diagnosis and management of DSD. Diagnostic tests
should be tailored according to the available informa-
tion. Unnecessary tests, especially those that require
anaesthesia for removal or are associated with radiation
exposure, should be limited to situations where a specic
question needs to be answered.
Parents and or patients should be made aware of the
paucity of well-designed studies, as these conditions are
rare. Unnecessary irreversible surgery should be post-
poned until a multidisciplinary experienced team, with
the parents and or patients approval, can make a
well-judged decision.
Source of funding
None.
Conict of interest
None.
31
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/
10.1016/j.aju.2012.11.008.
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